Discussion

The identified novel PPP1R13L variant, c.2368_2375dup p.(Pro793Glyfs*32), represents a single-base duplication that causes a frameshift and introduces a premature termination codon 32 amino acids downstream. This alteration is predicted to result in nonsense-mediated mRNA decay, effectively abolishing normal protein production. As a result, it meets the American College of Medical Genetics and Genomics PVS1 criterion at a very strong level (PVS1: null variant in a gene where loss of function is a well-established mechanism of disease). Additionally, the variant is absent from large population databases such as gnomAD, fulfilling the PM2 criterion at a moderate level (PM2: extremely low allele frequency in population databases, supporting rarity and potential pathogenicity). Initially, the variant was classified as likely pathogenic based on the combination of PVS1 and PM2. However, after a more detailed clinical investigation and careful comparison of the patient’s phenotype with the known features of PPP1R13L-related disease, the diagnosis became clinically definitive. The patient exhibited a highly specific phenotype that matched the gene-associated syndrome, allowing application of the PP4 criterion at a strong level (PP4_Strong: patient’s phenotype is highly specific for a disease with a single genetic aetiology). Incorporating this additional line of evidence led to the reclassification of the variant as pathogenic, underscoring the value of integrating genotype and phenotype data in accordance with American College of Medical Genetics and Genomics/AMP guidelines to ensure accurate diagnosis in rare Mendelian disorders.

Genetic factors play a central role in the aetiology of dilated cardiomyopathy, with more than 40 genes implicated, most commonly inherited in an autosomal dominant manner. ^{Reference Falik-Zaccai, Barsheshet and Mandel2} In a subset of patients, dilated cardiomyopathy occurs within a broader syndromic context involving extra-cardiac organ systems. Cardio-cutaneous syndromes, most notably Naxos and Carvajal syndromes, represent prototypical examples of this association, characterised by distinctive early-onset ectodermal features such as woolly hair and palmoplantar keratoderma, followed by the development of cardiomyopathy due to defects in desmosomal proteins. ^{Reference Falik-Zaccai, Barsheshet and Mandel2}

Pathogenic variants in PPP1R13L, encoding the iASPP protein, have recently been implicated in a distinct form of cardiocutaneous syndrome characterised by severe childhood-onset dilated cardiomyopathy with variable ectodermal features. iASPP, a member of the ASPP protein family, plays a pivotal role in stabilising desmosomes and the intermediate filament network through its interaction with desmoplakin and desmin, thereby maintaining cardiomyocyte integrity. This pathomechanism overlaps with that described in Naxos and Carvajal syndromes, in which desmosomal disruption leads to combined features of arrhythmogenic cardiomyopathy and dilated cardiomyopathy. ^{Reference Coudert, Thevenon and Testard5} Experimental models further support this link: Ppp1r13l-deficient mice develop right ventricular dilatation and sudden death with features of ARVC, while human myocardial samples demonstrate impaired desmoplakin–iASPP binding and reduced iASPP expression. ^{Reference Notari, Hu and Sutendra6}

Beyond its structural role, iASPP is essential for regulating NF-κB mediated inflammatory responses. Loss of function promotes excessive inflammation, maladaptive cardiac remodelling, and aggressive cardiomyopathy, consistent with observations in animal models. ^{Reference Falik-Zaccai, Barsheshet and Mandel2} Similarly, inflammation has been recognised as a complex and central contributor to the pathogenesis of arrhythmogenic cardiomyopathy. It may act not only as a secondary response to myocyte necrosis but also as an active driver of disease progression, even in the absence of infectious triggers or immune cell infiltration. Experimental models have shown that desmosomal gene pathogenic variants can intrinsically activate inflammatory pathways within cardiomyocytes, leading to structural instability, myocardial remodelling, and arrhythmogenesis. ^{Reference Meraviglia, Alcalde, Campuzano and Bellin7}

Clinical reports increasingly illustrate the pleiotropic spectrum of PPP1R13L-related disease. Tulbah et al. described a consanguineous family in which six children carrying a homozygous frameshift variant presented with dilated cardiomyopathy and woolly hair, several also exhibiting cleft lip/palate, developmental delay, or congenital glaucoma. ^{Reference Tulbah, Alruwaili and Alhashem3} Kalayinia et al. subsequently reported a stop gain variant associated with autosomal recessive arrhythmogenic cardiomyopathy, ^{Reference Kalayinia, Mahdavi, Houshmand, Hesami, Pourirahim and Maleki4} and Coudert et al. expanded the phenotypic spectrum of PPP1R13L-related disease by describing patients with biallelic variants and anorectal malformations, including imperforate anus in one case and an intermediate-type anorectal anomaly in another. ^{Reference Coudert, Thevenon and Testard5} Robinson et al. reported 7 children from 5 unrelated families who had severe dilated cardiomyopathy, with or without ectodermal or neurodevelopmental features, and pathogenic variant in the PPP1R13L gene. One patient experienced sustained ventricular tachycardia. Three of the children died before 5 years of age due to progression of heart failure; 3 underwent cardiac transplantation, and 1 was awaiting transplant. In 4 of the children, hair was described as sparse/thin and wiry, curly, or woolly, and 2 children had dystrophic nails. Cleft lip and palate were present in 2 brothers. ^{Reference Robinson, Zaklyazminskaya and Povolotskaya1} Similarly, Henry et al. reported a three-year-old girl with a homozygous PPP1R13L pathogenic variant who developed inotrope-dependent heart failure during viral infections, eventually requiring left ventricular assist device placement. She exhibited classic ectodermal features including wiry hair, bifid central incisors, and recurrent paronychia, in addition to gastrointestinal anomalies such as constipation and rectal prolapse. ^{Reference Henry, Bernhardt, Hayes and Mitchelson8}

Our patient displayed a comparable phenotype, with rapidly progressive dilated cardiomyopathy accompanied by ectodermal features including sparse hair, craniofacial dysmorphism, and abnormal dentition. Importantly, malignant ventricular arrhythmias culminating in sudden cardiac death suggest that, as in other desmosomal cardiomyopathies, the dilated phenotype may represent the terminal stage of an arrhythmogenic process. Persistent elevation of cardiac troponin levels in our patient, despite anti-inflammatory treatment and intravenous immunoglobulin administration, may reflect ongoing myocardial injury and active disease progression. Rather than reflecting only acute myocardial injury, sustained troponin elevation may indicate chronic subclinical inflammation, ongoing myocyte apoptosis, or adverse remodelling, particularly in the context of genetic cardiomyopathies. In PPP1R13L-related disease, where inflammation and desmosomal instability play central roles, persistent troponin elevation may serve as a surrogate for the severity and progression of the cardiomyopathic process.

PPP1R13L pathogenic variants are listed in OMIM as “Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities” underscoring the intrinsic arrhythmogenic substrate irrespective of left ventricular size. Thus, recognition of this entity has major implications for clinical management.